A retrospective cohort study. To calculate the magnitude of any increased risk of epidural hematoma (EDH) associated with chemoprophylactic anticoagulation (chemoprophylaxis), if any. Chemoprophylaxis for the prevention of venous thromboembolic events may be associated with an increased risk of EDH after spine surgery. A total of 6869 consecutive spine surgeries performed at our institution were identified, and clinical and demographic data were collected. We identified cases in which symptomatic EDHs were evacuated within 30 days postoperatively. Patients receiving chemoprophylaxis and controls were matched using K-nearest neighbor propensity score matching to calculate the effect of anticoagulation on the rate of postoperative EDH. After propensity score matching, 1071 patients who received chemoprophylaxis were matched to 1585 controls. Propensity scores were well balanced between populations (Rubin B=20.6, Rubin R=1.05), and an 89.6% reduction in bias was achieved, with a remaining mean bias of 3.2%. The effect of chemoprophylaxis on EDH was insignificant ( P =0.294). Symptomatic EDH was independently associated with having a transfusion [odds ratio (OR)=7.30 (1.15, 46.20), P =0.035], having thoracic-level surgery [OR=41.19 (3.75, 452.4), P =0.002], and increasing body mass index [OR=1.44 (1.04, 1.98), P =0.028] but was not associated with chemoprophylaxis. Five out of 13 patients who developed EDH (38.5%) were receiving some form of anticoagulation, including 1 patient on therapeutic anticoagulation, 1 concurrently on aspirin and chemoprophylaxis, and 2 who were also found to have developed thrombocytopenia postoperatively. The median time on anticoagulation before EDH was 8.1 days. A higher proportion of patients who developed EDH also developed venous thromboembolic events than the general population [38.5% vs. 2.4%, OR=25.34 (9.226, 79.68), P <0.0001], and 1 EDH patient died from pulmonary embolism while off chemoprophylaxis. Chemoprophylactic anticoagulation did not cause an increase in the rate of spinal EDH in our patient population.